Mechanisms of Disease I: Cell Growth and Cell Differentiation
Learning Objectives:
Explain the cell cycle, its checkpoints and its regulation by both mitogenic and
growth inhibitory factors.
Define drugs acting on the cell cycle
Explain key molecular events in the regulation of the cell cycle and apoptosis
Explain mechanisms by which growth control can be disrupted in neoplasia
Define the response to DNA damage
Diseases related to cell growth & differentiation fall into 3 groups: Developmental
conditions (e.g. neural tube defect → spina bifida), Neoplasia & metaplasia (e.g.
cancer, tumours) and others (e.g. cardiac hypertrophy)
2 main forms of cell growth: Hypertrophy & Hyperplasia
Hypertrophy: Cells growing bigger = more proteins & membranes. Protein synthesis
is a big driver for increased cell size
Hyperplasia: More cells - caused by cell division/proliferation
Differentiation happens after a cell leaves the cell cycle = differentiated cells are
'post-mitotic'
Cell growth and differentiation are governed by the integration of intra &
extracellular signals
o These signals converge on promoters of key genes
Types of proteins and their effects in cell growth & differentiation:
Proteins that stimulate proliferation and promote survival are called mitogens (e.g.
growth factors & interleukins)
Proteins can induce differentiation and inhibit proliferation (e.g.TGFb)
Some proteins can do either (e.g. Wnt ligands)
Some proteins can induce apoptosis (e.g. TNFa)
Checkpoint controls in a cell cycle involve specific protein kinases and phosphatases
CDK + Cyclin → Active Cyclin-CDK complex
o Which phosphorylates specific substrates & regulates the cell cycle
o This complex can be regulated by the binding of Cyclin-CDK inhibitors (CDKIs)
Retinablastoma protein (RB) - is a key substrate of G1 & G1/S cyclin-dependent kinases
Unphosphorylated RB binds to E2F transcription factor → prevents stimulation of S-
phase protein expression → prevents DNA replication
Released E2F → stimulates expression of S-phase proteins → DNA replication starts
What if there's DNA damage?
1. Stop the cycle (with CDKIs)
2. Attempt DNA repair (e.g. mismatch repair)
3. If repair impossible → programmed cell death
Learning Objectives:
Explain the cell cycle, its checkpoints and its regulation by both mitogenic and
growth inhibitory factors.
Define drugs acting on the cell cycle
Explain key molecular events in the regulation of the cell cycle and apoptosis
Explain mechanisms by which growth control can be disrupted in neoplasia
Define the response to DNA damage
Diseases related to cell growth & differentiation fall into 3 groups: Developmental
conditions (e.g. neural tube defect → spina bifida), Neoplasia & metaplasia (e.g.
cancer, tumours) and others (e.g. cardiac hypertrophy)
2 main forms of cell growth: Hypertrophy & Hyperplasia
Hypertrophy: Cells growing bigger = more proteins & membranes. Protein synthesis
is a big driver for increased cell size
Hyperplasia: More cells - caused by cell division/proliferation
Differentiation happens after a cell leaves the cell cycle = differentiated cells are
'post-mitotic'
Cell growth and differentiation are governed by the integration of intra &
extracellular signals
o These signals converge on promoters of key genes
Types of proteins and their effects in cell growth & differentiation:
Proteins that stimulate proliferation and promote survival are called mitogens (e.g.
growth factors & interleukins)
Proteins can induce differentiation and inhibit proliferation (e.g.TGFb)
Some proteins can do either (e.g. Wnt ligands)
Some proteins can induce apoptosis (e.g. TNFa)
Checkpoint controls in a cell cycle involve specific protein kinases and phosphatases
CDK + Cyclin → Active Cyclin-CDK complex
o Which phosphorylates specific substrates & regulates the cell cycle
o This complex can be regulated by the binding of Cyclin-CDK inhibitors (CDKIs)
Retinablastoma protein (RB) - is a key substrate of G1 & G1/S cyclin-dependent kinases
Unphosphorylated RB binds to E2F transcription factor → prevents stimulation of S-
phase protein expression → prevents DNA replication
Released E2F → stimulates expression of S-phase proteins → DNA replication starts
What if there's DNA damage?
1. Stop the cycle (with CDKIs)
2. Attempt DNA repair (e.g. mismatch repair)
3. If repair impossible → programmed cell death
